Abstract LB-256: Clonogenic growth of androgen receptor-overexpressing models of castration recurrent prostate cancer cells becomes insensitive to receptor ligands when their complete cellular secretory milieu is restored

Abstract

Abstract Evidence that androgen receptor (AR) overexpression causes castration recurrent prostate cancer (CRPC) cells to thrive on minimal residual post-castrate androgen is derived from studies of in vitro colony formation in the absence of cell-secreted factors or from studies demonstrating synergy between androgen and individual signaling pathways in isolation. We examined androgen-dependence using in vivo generated CRPC model cells overexpressing full length AR (C4-2 cells) or co-expressing a splice-variant (22Rv1 cells). The cells showed robust colony formation in conditioned media lacking androgenic activity derived from the same cells or from HEK293 fibroblasts. This effect was (i) not enhanced by androgen (ii) insensitive to blocking ligand-dependent transcriptional activity of AR, (iii) insensitive to mifepristone (iv) AR-dependent, (v) associated with AR phosphorylation and (vi) similar to androgen-stimulation in sensitivity to signaling pathway inhibitors. This ligand-insensitive response of overexpressed AR to the total cellular secretory complement may limit interventions targeting hormonal factors in CRPC. Citation Format: Mugdha Patki, Yanfang Huang, Manohar Ratnam. Clonogenic growth of androgen receptor-overexpressing models of castration recurrent prostate cancer cells becomes insensitive to receptor ligands when their complete cellular secretory milieu is restored. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-256.